The isolated perfused canine brain preparation will be used in this study because it allows control of blood flow and plasma metabolite levels while eliminating interference from extracerebral circulation and metabolism. Stimultaneous measurements of CMRO2 and CMRglu will be made during and after arterial hypoxia. The data will be correlated with the tissue levels of adenine nucleotides, creatine phosphate and glycolytic intermediates in order to provide a comprehensive understanding of the metabolic events during cerebral hypoxemia. The preparation will be used to study unidirectional transport of glucose, fatty acids and selected drugs at the blood-capillary endothelial cell interface using an indicator dilution method with 99Tc sodium pertechnitate as the intravascular reference and 3H-labeled compounds as test molecules. Cerebral glucose transport will be characterized in terms of its flow dependence and its response to antidiuretic hormone, angiotensin, serotonin and epinephrine. In the intact brain, several fundamental values concerning glucose metabolism such as the volume of cerebral extracellular glucose space, the glucose concentration in that space and rate constants for glucose movement between the capillary endothelium, the extracellular space and brain tissue are inaccurately known. We plan to refine the computer-based model used in conjunction with the indicator dilution data and study glucose compartmentation, and the associated rate constants during pathologic derangements of cerebral metabolism. The role of perivascular adrenergic neurons in the control of cerebrovascular resistance (CVR), and cerebral capillary function will be studied and the receptors involved in catecholamine-mediated changes in CVR will be pharmacologically characterized.